Amino-acylamino-acylamino-penicillanic acids



United States Patent 3,340,252 AMINO-ACYLAMINO-ACYLAMINO- PENICILLANIC ACIDS Harvey E. Alburn, West Chester, and Norman H. Grant,

Wynnewood, Pa., assignors to American Home Products Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Apr. 7, 1964, Ser. No. 358,050 20 Claims. (Cl. 260239.1)

This invention relates to new synthetic penicillins having potent activity against Gram-negative and Grampositive microorganisms.

In our copending patent application Ser. No. 353,574, filed Mar. 20, 1964, now patent No. 3,268,513 and of which the present application is a continuation-in-part, there is disclosed a novel method for preparing aminoacylamino-acylamino penicillanic derivatives.

With the use of the method described in the said copending application, there has been discovered a series of new penicillanic acid derivatives having the formula:

where subwhere R is of the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkaryl, and substituted alkaryl; and

R is of the group consisting of alkyl and aryl;

NH, where n=2 to 9;

4 HNR where:

R R R and R are of the group consisting of hydrogen,.a1kyl, nitro, sulfo, amino, halo and hydroxy;

R and R R and R and R and R when respectively joined, complete a ring of the group consisting of aryl and alicyclic; and

R is of the group consisting of hydrogen and lower alkyl;

CHz-CH-CO ice 11:1 to 5, and R is of the group consisting of (a) hydrogen, alkyl, and (b) A-C O- |3H-(CH;) -s- NHz in which case A is a second residue of the penicillanic acid derivative of Formula I above, and

n"=1 to 5;

( rim H%OO- L NH where:

R is of the group consisting of hydroxy and alkyl, and n=2 to 7; and

NH: where n=1 to 4;

Said compounds are useful for treatment of infectious diseases caused by Gram-positive and Gram-negative bacteria, upon either parenteral or oral administration. They also have use as nutritional supplements in animal feed.

The general process for preparing the aforesaid novel amino-acylamino-acylamino-penicillanic acids is described and claimed in said copending application and comprises generally the reaction of a 4-substituted-2,5-oxazolidinedione (also known as an N-carboxy-amino acid anhydride) with a 6-(amino-acylamino)-penicil1anic acid under controlled conditions. Methods for the preparation of the N-carboxy amino acid anhydride and 6-(aminoacylamino)-penicillanic acid reactants suitable for use in the process are also described in or referred to in said copending application.

In a preferred method for preparing the amino-acy1- a-mino-acylamino-penicillanic acids of the present invention, the 4-substituted-2,S-oxazolidinedione chosen is reacted with the selected 6-(a-amino-acylamino)-penicil lanic acid in approximately equimolar quantities in a cold aqueous solution in a pH range from about 3.8 to about 7.4 and preferably in the range 4.7-7.0. The mixture is stirred for several hours at a temperature from just above the freezing point of the aqueous mixture to about 37 C., and preferably in the range 0-10 C. Although not essential, it may be preferred to include a buffer having an ionic strength of about 0.02, preferably about 0.3, to aid in keeping the reaction mixture within the required pH range. Suitable buffers for maintaining the desired pH may be any mixture of organic or inorganic water-soluble acids, bases, or salts such as sodium acetate-acetic acid, calcium acetate-acetic acid, pyridineacetic acid, formic acid-ammonia, etc. Alternatively, the reaction mixture may be maintained within the requisite pH range by careful addition of a base such as NaOH or the like.

The following examples are illustrative of the invention, but are not to be considered necessarily limitative thereof.

3 Example l.-6-[DL-Z-(o-aminobenzamide)-N-methyl- Z-phenylacetamido] penicillanic acid Mix 290 mg. (0.8 millimole) of 6-(DL-N-methyl-2- aminophenylacetamido)-pencillanic acid With 130 mg. (0.8 millimole) of isatoic anhydride in 200 ml. of icecold water. Stir at 12 for 60 minutes, keeping the pH at 6.0 by the addition of 1 N NaOH. Filter, and freezedry the filtrate. The product is active against Staph. aureas and E. coli.

Example II.--6- [DL -2-(2-amin0-5- nitro'benzamido yN- methyl-Z-phenylacetamido] penicillanic acid Mix 290 mg. (0.8 millimole) of 6-(DL-N-methyl-2- aminophenylacetamido)penicillanic acid with 165 mg. (0.8 millimole) of 6-nitroisatoic anhydride in 20 ml. of ice-cold Water. Stir at 1-2 for 60 minutes, keeping the pH at 6.0 by the addition of 1 N NaOH. Filter, and freeze-dry the filtrate. The product is active against Staph. aureas and E. coli.

Example III.6- [DL-2-(Z-amino-S-methyl-N-methylbenzamido)-2-phenylacetamidolpenicillanic acid Mix 363 mg. (1 millimole) of 6-(DL-N-methyl-2- aminophenylacetamido)penicillanic acid with 151 (1 millimole) of 6-methylisatoic anhydride in 25 ml. of ice-cold water. Stir at 1-2 for 60 minutes, keeping the pH at 6.0 by the addition of 1 N NaOH. Filter, and freeze-dry the filtrate. The product is active against both Gram-positive and Gram-negative organisms.

Example IV When in the procedure of Example II, the N-carboxyanhydride of S-nitroanthranilic acid is replaced by 0.8 millimole of the N-carboxyanhydride of (1) 1-aminocyclopropanecarboxylic acid (2) 1-aminocyclodecanecarboxylic acid (3) 2-amino-3-naphthoic acid (4) 2-methylamino-5-nitrobenzoic acid (5) L-a-aminO-S-methylindole-3-propionic acid (6) L-a-aminO-S-ethylindole-3-propionic acid (7) L-a-aminO-S-methoxyindo1e-3-propionic acid (8) D-2-amino-3-(ethylthio)-propionic acid (9) DL-2-amino-3-(methylthio -propionic acid (10) DL-2-amino-7-(methylthio)-heptanoic acid (11) D-ethionine 12) DL-Z-ethylamino-2-phenylglycine 13 DL-2-amylamino-Z-phenylglycine 14) 2-carboxytrimethyleneimine 15 2-carboxyoctamethyleneimine the corresponding penicillin derivatives, all active against Gram-positive and Gram-negative microorganisms, are produced.

Example V When in the procedure of Example I, the 6-(DL-N- methyl-2-aminophenylacetamido)penicillanic acid is replaced by 0.8 millimole of 6-(Z-anilinoacetamido)penicillanic acid and the isatoic anhydride by glycine-N-carboxy anhydride, there is produced 6-[2-(D-2-amino-N- phenylacetamido)acetamido]penicillanic acid, Which is active against both Gram-positive and Gram-negative microorganisms.

Example VI When in the procedure of Example V, the 6-(2-anilinoace'tamido)penici1lanic acid is replaced by 0.8 millimole of 6 (DL-N-ethyl-Z-aminophenylacetamido)penicillanic acid, the corresponding penicillin product, active against both Gram-positive and Gram-negative microorganisms, is produced.

' Example VII When in the procedure of Example V, the 6-(2-ani1inoacetamido)penicillanicacid is replaced by 0.8 millimole of 6 (DL-N-amyl-Z-aminophenylacetamido)penicillanic acid, the corresponding penicillin product, active against both Gram-positive and Gram-negative microorganisms, is produced.

Example VIII .6-[L-2-(D-2-amin0-2-phenylacetamida)- 4-methy lvaleram'id0]penicillanic acid Mix 395 mg. (1.2 millimoles) of 6-(L-2-amino-4- methylvaleramido)penicillanic acid With 212 mg. (1.2 millimoles) of D-phenylglycine-N-carboxyanhydride in 30 ml. of ice-cold water. Stir at 12 for 60 minutes, keeping the pH at 6.0 by the addition of 1 N NaOH. Filter, and freeze-dry the filtrate. The product is active against Staph. aureus and E. coli.

Example IX.-6-[2-(D-2-amino-4-methylvaleramido acetamido] penicillanic acid Mix 218 mg. (0.8 millimole) of 6-(2-aminoacetamido)-penicillanic acid with 126 mg. (0.8 millimole) of the N-carboxyanhydride of D-leucine in 20 m1. of ice-cold water. Stir at 1-2 for 60 minutes, keeping the pH at 6.0 by the addition of 1 N NaOH. Filter, and freeze-dry the filtrate. The product is active against both Staph. aurews and E. coli.

Example X When in the procedure of Example 1X, the N-carboxyanhydride of D-leucine is replaced by 0.8 millimole of the N-carboxyanhydride of Glycine D-phenylglycine D-phenylalanine L-phenylalanine 1-amin-ocyclobutanecarboxylic acid 1-aminocyclopentanecarboxylic acid 1-aminocyclohexanecarboxylic acid (8) 1-aminocyclooctanecarboxylic acid (9) Ant'hranilic acid (10) Z-amino-S-nitrobenzoic acid 1 1 2-arnino-5-chlorobenzoic acid (12) D-trypt-ophan (13) L-tryptophan ('14) L-cystine l5 DL-phenylsarcosine (16) N-phenyl'glycine (l7) DL-o-ethoxyphenylglycine respectively, the following corresponding penicillin derivatives, all active against Gram-positive and Gram-negative microorganisms, are produced:

5 (15) ,6 [2-(DL-Z-amino-N-methyl-Z-phenylacetamido) acetamido] penicillanic acid 16) 6-[2 (2 anilinoacetamido) acetamido1penicillanic acid (17) 6 [2 (DL-2-amino-2-o-ethoxyphenylacetamido) acetamido]penicillanic acid Example X I .6- [D-Z-(Z-aminoacetamido) -4-methylvaleramid]penicillanic acid Mix 263 mg. (0.8 millimole) of 6-(D-2-amino-4-methylvaleramido) penicillanic acid with 80 mg. (0.8 millim'ole) of the N-car-boxyanhydride of glycine in 20 ml. of icecold water. Stir at 1-2" for 60 minutes, keeping the pH at 6.0 by the addition of 1 N NaOH. Filter, and freezed-ry the filtrate. The product is active against both Staph. aureus and E. coli. I

Example XII When in the procedure of Example XI, the N-carboxyanhydride of glycine is replaced by 0.8 millimole of the N-canboxyanhydride of respectively, the following corresponding penicillin derivatives, all active against Gram-positive and Gram-negative microorganisms, are produced:

( 1) 6 [D-2-(D-2-amino-4-methylvaleramido)-4-methylvaleramido]penicillanic acid (2) 6 D-2-(D-2-amino-2-phenylacetamido) -4-methy1- valeramido]penicillanic acid (3) 6 [D 2(D-2-amino-3-phenylpropionamido)Amethylvaleramido1penici1lanic acid (4) 6 [D-2-(L-Z-amino-3-phenylpropionamido)-4-methylvaleramidoJpenicillanic acid (5) 6 [D-2-(1-aminocyclobutanecarboxamido)-4-rnethylvaleramido]penicillanic acid ('6) 6 [D-2-(1-aminocyclohexanecarboxamido)-4-methylvaleramido]penicillanic acid (7) 6 [D-Z-(Z-aminobenzamido) -4-methylvaleramido] penicillanic acid (8) 6 [D-2-(Z-amino-S-nitrobenzamido)-4-methylvaleramidoJpenicillanic acid (9) 6 D 2-(D-a-aminoindole-3-propionamido) 4-methylvaleramido1penicillanic acid (10) 6 [D-2(-L-u aminoindole-3-propionamido) 4-meth- -ylvaleramido]penicillanic acid (11) 6 [D-2-[D-2a1nino-4-(methy1thio)butyramido]-4- methylvaleramido]penicillanic acid (12) Bis[ 6 (D 2-[L-3-thio2-aminopropionamido]-4- methylvaleramido)]penicill anic acid (13) 6 [D 2-(DL-2-amino-N-methyl-2-phenylacetamido -4-methylvaleramido] penicillanic acid 14) 6 [D-2-(2-anilinoacetamido)-4-methylvaleramido] penicil-lanic acid Example XIll.-6-[L-2-(D-Z-amino-Z-phenylacetamido) phenylpropionamido] penicillanic acid Mix 436 mg. (1.2 millimoles) of G-(L-Z-aminophenylpropion'amido)penicillanic acid with 212 mg. (1.2 millimoles) of D-phenylglycine-N carboxyanhydride in 30 ml. of ice-cold water. Stir at 12 for 60 minutes, keeping the 6 pH at 6.0 by the addition of 1 N NaOH. Filter, and freezedry the filtrate. The product is active against Staph. aureus and E. coli.

Example XIV.-6- [D-Z-(Z-aminoacetamido) -2-phenylacetamido] penicillanic acid Mix 420 mg. (1.2 millimoles) of 6-( D-2-amino 2- phenylacetarnido)penicillanic acid with 121 mg. (1.2 millimoles) of glycine-N-canboxyanhydride in 30 ml. of icecold water. Stir at 12 for 60 minutes, keeping the pH at 6.0 by the addition of 1 N NaOH. Filter, and freezedry the filtrate. The product is active against both Staph. aureus and E. coli.

Example XV When in the procedure of Example XIV, the N-carboxyanhydride of glycine is replaced by 1.2 millimoles oi the N-cai1boxyanhydride of (1) D-ileucine (2) L-leucine (3) D-phenylglycine (4) D-phenylalanine (5) L-phenylalanine (6) 1-aminocyclolbutanecarboxylic acid (7) l-aminocyclopentanecafiboxylic acid (8) 1-'aminocyclo'hexane-carboxylic acid (9) 1-aminocyclooctanecanboxylic acid (10) Z-amino-S-nitrdbenzoic acid Z-amino-S-chlorobenzoic acid (12) Z-amino-S-methyl-benzoic acid (13) D-tryptophan 14) L-trypt ophan (15) D-methionine (16) DL-phenylsarcosine (17) N-phenylglycine (18) DL-gl utamine 19) DL-o-ethoxyphenylglycine (20) cystine (21) anflhranilic acid respectively, the [following corresponding penicillin derivatives, all active against Gram-positive and Gram-negative microorganisms, are produced:

( 1 6-[D-2-(D-2-amino-4-methylvaleramido) -2- phenylacetaimido]penicillanic acid (2) 6-[D-2-(L-Z-amino-4-methy1valeramido)-2- phenylacetamid'o]penicillanic acid (3 6- [D-2- (D-Z-amino-Z-phehylacetamido) -2-phenylacetamido] penicillanic acid (4) 6-[D-Z-(D-2-amino-3-phenylpropionamido)-2- qnhenylacetamido]penicillanic acid 5 6- [D-2- (L-2-amino-3 -pl1enylpropi-onamid0)-2- phenylacetamido]penicillanic acid (6) 6- [D-2- 1-amino-cyc1obutai1ecarboxamido)-2- phenylacctasmido]penicillanic acid (7 6- [D-2-( 1-aminocyclopentanecarboxamido) -2- phenylacetamido]penicilulanic acid (8) 6- [D-2-( 1-amino-cyclohexanecarboxamido) -2- phenylacetamido]penicill'anic acid 9) 6- [D-2-( 1-amino cyclooctane-carboxamido) -2- phenylacetamido]peniciilanic acid 10) 6- [D-2- (2-amino-5-nitro benzcic) -2-phenylacetan1ido]penicillanic acid (1 1) 6-[D-2-(Z-amino-S-chlorobenzamido)-2-phenylacetamido]penici11anic acid (12) 6-[D-2-(2-amino-S-rnethylbehzamido)-2-phenylacetamido]penicillanic acid (13) 6-[D-2-(D-a-aminoindole-3 propionamido) -2- phenylacetamido]penicillanic acid 14) 6- [D-2- (L-a-aminoindole-3-propion-amido) -2- phenylacetamido]penicillanic acid 15) 6- [D-2-(D-2-amino-4-methylthiobutyramido) -2- phenylacetamido1penicillanic acid 16) 6- [D-2-(DL-2-amino-Nmethyl-Z-phenylacetamido)-2-pheny1lacetamido]penicillanic acid 17 6- [D-2- (2-anilinoa'cet'amido) -2phenylacetamido] penicillanic acid 18) 6- [D-2- (DL-Z-amihoglutaramido -2-phenylacetamido]'penicillanic acid (19) 6- [D-2- (DL-2-amino-Z-o-ethoxyphenylacetamido) 2-pheny1acetamido]penicillanic acid (20) bis[6-(D-2-[L-3-thio-2-aminopropionamido1-2- phenylacetarnido]penicillanic acid (21) 6-[D-2-(2-aminobenzamido)-2-phenylacetamido] penicillanic acid Example XVI When in the procedure of Example III, the 6-methylisatoic anhydride is replaced by 6-sulfoisatoic anhydride,

the corresponding derivative is obtained.

Example XVII When in the procedure of Example IX, the N-canboxyanhydride of D-leucine is replaced by 0.8 millimole of the N-canboXyanhydr-ide of (1) 1-aminocyclopropanecatrboxylic acid (2) 1-a1ninocyclodecanecar boxylic acid (3) 2-amino-3-naphthoic acid (4) 2-methylamino-5-nitrobenzoic acid (5) L-a-amino-5-methylindole-3-propionic acid (6) L-u-amino-5-ethylindole-3-propionic 'acid (7) L-a-amino-5-methoxyindole-3-propionic acid (8) D-2-amino-3-(ethylthio)-propionic acid (9) DL-2-amino-3-(methylthioypropionic acid 10) DL-2-amino-7- (methylthio heptanoic acid (11) D-ethionine (12) DL-2-ethylamino-Z-phenylglycine 13) DL-Z-amylamino-2-phenylglycine (14) 2-carboxytrimethyleneimine (15 2-carboxyoctamethyleneimine the corresponding penicillin derivatives, all active against Gram-positive and Gram-negative microorganisms, are produced.

Example XVIII When in the procedure of Example XIV, the N-carboxyanhydride of glycine is replaced by 1.2 millimoles of the N-carboxyanhydride of 1-aminocyclopropanecarboxylic acid 1-aminocyclodecanecarboxylic acid 2-amino-3-naphthoic acid 2-methylamino-S-nitrobenzoic acid L-u-aminO-S-methylindole-3-propionic acid L-u-amino-S-ethylindole-El-propionic acid L-u-amino-5-methoxyindole-3-propionic acid (8) D-Z-amino-B-(ethylthio)-propionic acid (9) DL-2-amino-3-(methylthio) propionic acid (10) DL-2-amino-7-(methy1thio)-heptanoic acid (11) D-ethionine (12) DL-2-ethy1amino-2-phenylglycine 13) DL-Z-amylamino-2-phenylglycine (14) 2-carboxytrimethyleneimine 15 2-carboxyoctamethyleneimine the corresponding penicillin derivatives, all active against Gram-positive and Gram-negative microorganisms, are produced.

Example X IX .-6- [D-Z-(D-Z-am inO-Z-phenyZacetyZ) amino-Z-phenylacetwmido penicillanic acid Mix 50 mg. of ampicillin and mg. of D-phenylgly: cine in 5 ml. of 0.1 M sodium acetate-acetic acid buffer at pH 4.7. Stir at 1 C. for 2 hours. Filtrate and concentrate, after which agar plate assays against E. coli and hydroxylamine determinations of total fi-lactam demonstrate the formation of the new antibiotic having the following elemental analysis:

Found: C, 58.6; H, 5.60; N, 11.20; S, 6.2. Calculated for C H O N S: C, 59.8; H, 5.39; N, 11.61; S, 6.64.

X is of the group consisting of hydrogen, lower alkyl,

phenyl, and phenyl lower alkyl; X is of the group consisting of hydrogen, lower alkyl,

and phenyl; and Y is of the group consisting of:

R -OH-G 0 wherein:

R is of the group consisting of hydrogen, lower alkyl, phenyl, (lower)alkylphenyl, (lower)alkoxyphenyl, aminophenyl, nitrophenyl, chlorophenyl, indolo(lower)a1kyl, (lower) alkylindolo(lower)a1kyl, and (lower) alkoxyindolo(lower) alkyl; and

R is of the group consisting of hydrogen, lower alkyl,

and phenyl;

(OHZ)B "-0 O'- NH: where 11:2 to 9; 3)

wherein:

R R R and R are of the group consisting of hydrogen, alkyl, sulfo, nitro and chloro; R and R when joined complete a naphthylene ring;

and R is of the group consisting of hydrogen and lower alkyl;

NHz Ra N H R4 where R R R and R are of the group consisting of hydrogen, lower alkyl, and lower alkoxy; R-som) n-r ln-o o NH: where:

21:1 to 5, and R is of the group consisting of hydrogen and lower alkyl;

(0H2). Ell-0O- NH where R is of the group consisting of hydroxy and alkyl, and

n=2 to 7; and

(7) HaN-C O-(G H2) nCH-0 0- wherein n=l to 2.

2. 6-[DL-2-(2 amino-S-methyl-N-methylbenzamido)- 2-phenylacetamido]penicillanic acid.

3. 6-[L-2-(D 2-amino-2-phenylacetamido)-4-methylva1eramido1penicillanic acid.

4. 6 [D 2 (D 2 amino 2 phenylacetamido) 2-phenylacetamido]penicillanic acid.

5. 6 [D 2 (D 2 amino 3 phenylpropionamido) 2-phenylacetamido]penicillanic acid.

6. 6 [D 2 (1 amino-cyclobutanecarboxamido) 2-phenylaceta-mido]penicillanic acid.

7. 6 [D 2 (1 amino-cyclopentanecarboxamido) 2-pheny1acetamido] penicillanic acid.

8. 6 [D 2 (1 amino-cyc1ohexanecarboxamido) 2-phenylacetamido] penicillanic acid.

9. 6 [L 2 (D 2 amino-2-pheny1acetamido) phenylpropionamido] penicillani-c acid.

10. 6 [2 (D 2 amino 2 phenylacetamido) acetamido1penici1lanic acid.

11. 6 [2 (1 aminocyclobutanecarboxamido)acetami-do]penicillanic acid.

12. 6 [2 1 aminocyclopentanecarboxamido) acetamidojpenicillanic acid.

13. 6 [2 (1 aminocyclohexanecarboxamido)acetamidoJpenicillanic acid.

14. 6 [D 2 (D 2 amino-Z-phenylacetamido)-4- methyl-valeramido] penicillanic acid.

15. 6 [D 2 (1 aminocyclobutanecarboxamido) 4-methylvalera-mido]penicillanic acid.

16. 6 [D 2 (1 aminocyclopentanecarboxamido) 4-methylvaleramido] peni-cillanic acid.

17. 6 [L 2 (D 2 amino-Z-phenylacetamidO) 2-pheny1acetamido]penicil1anic acid.

18. 6 [L 2 (D 2 aminoindole-3-propionamido) Z-phenylacetamido]penicil1anic acid.

19. 6 [L 2 (D-Z-amino-4-methy1thiobutyramido) Z-phenylacetamido]penicillanic acid.

20. 6 [L 2 (D 2-amino-2-phenylacetamido)-3- phenylpropionamido]penicillanic acid.

No references cited.

NICHOLAS S. RIZZO, Primary Examiner. 

1. A COMPOUND OF THE FORMULA 